Project Summary/Abstract This proposal aims to provide advanced career development and training to the applicant. The principal investigator (PI) has previously received PhD training in bioenergetics and exercise science, and has received postdoctoral training in urology under the mentorship of Dr. Arthur Burnett, a recognized leader in the basic science of erectile dysfunction. The PI will receive further training from Dr. Solomon Snyder, an internationally recognized leader in neurotransmission with a strong track record of training successful scientists. The proposed training plan will provide continued refinement of the PI?s scientific, technical, and professional skills and aid in his transition to independence. The PI will take advantage of the vast training and professional development resources at the Johns Hopkins School of Medicine. The proposed research seeks to identify the potential role of hydrogen sulfide (H2S) as a regulator of erectile function. We have previously established a rodent model of Western diet-induced erectile dysfunction (ED). Initial investigations suggest that excessive protein nitrosylation (binding of nitric oxide (NO) to protein thiols) accelerates the ED development in response to the Western diet. The Western diet also diminishes production of hydrogen sulfide (H2S) in erectile tissue. Our research team has previously demonstrated that H2S exerts cell signaling through protein sulfhydration (binding of H2S to thiols), which often opposes the effects of nitrosylation. Use of a recently developed technique to measure in vivo reactive oxygen species indicates that the Western diet increases penile free radical production, which is accelerated by nitrosylation. H2S has previously been reported to have antioxidant properties and that signaling by sulfhydration may protect against damaging effects of excessive amounts of free radicals. Thus, we hypothesize that diminished H2S production resulting from the Western diet is a key factor in the development of ED. In this proposal, we are aiming to understand how H2S affects the redox state of the penis by examining levels of enzymes that produce H2S, measuring penile free radicals, and investigating sulfhydration signaling in pathways that regulate antioxidant capacity. We are also aiming to understand how the interplay between H2S action and nitrosylation impacts protein kinase G signaling and erectile function. To address these aims, we will use genetically modified mouse models of diminished H2S production, enhanced H2S production, excessive nitrosylation, and altered protein kinase G signaling. Mice will be exposed to a Western diet, and oral therapies to enhance H2S production will be investigated as a potential therapy to treat ED.